P1406: SAFETY AND EFFICACY OF IBI346, A FIRST-IN-CLASS BCMA-TARGETING MODULAR CAR-T CELL THERAPY, FOR PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): PRELIMINARY RESULTS FROM TWO PHASE I STUDIES
Authors: Chengcheng Fu, Chunrui LI, DI Wang, Song Jin, Weiqin Yao, Jingjing Shang, Shuang Yan, Min Xiao, Liting Chen, Miao LI, Huafeng Wei, Jia Duo, Lingge Cheng, Nana Luo, Yongfang Sui, Dan Xu, Chunyan Yang, Lin Zhu, Christian Klein, Depei Wu
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Chimeric antigen receptor (CAR)-T cell therapy targeting B-cell maturation antigen (BCMA) has achieved great success in treating RRMM; however, since current CAR-T cells based on 2nd-generation CAR formats directly recognize and kill tumor cells, they lack control over their in vivo activity, which may induce a long-lasting "on-target off-tumor effect" even if tumor cells are completely eradicated. We previously developed the P329G-CAR-T cell approach, a modular and switchable CAR technology by which the modular CAR-T cells indirectly bind tumor antigens via an Fc-silent tumor-targeting human antibody containing the P329G (PG) mutation in the Fc portion as an adapter molecule, allowing to control CAR-T cell activity. Here, we reported the first-in-human results of the BCMA-targeting P329G-CAR-T product IBI346. Aims: To report the preliminary safety, tolerability, antitumor activity, and pharmacokinetic characteristics from the dose escalation parts of two investigator sponsored phase I studies evaluating IBI346 in patients (pts) with RRMM. Methods: The key inclusion criteria for both studies were pts with RRMM with ≥3 prior lines of anti-myeloma therapy and measurable disease. In IBI346Y001 (Y1) study (NCT05270928), pts received an intravenous (IV) injection of IBI346 antibody at escalating doses of 0.3/1/3 mg/kg on day 1 Q3W and a single IV infusion of IBI346 CAR-T cells at a fixed dose of 2×106 cells/kg on day 2 at 1st cycle. In IBI346Y002 (Y2) study (NCT05266768), pts received IBI346 antibody at escalating doses of 0.1/0.3/1/3 mg/kg on day 1 Q1W at the first three weeks followed by Q3W thereafter and IBI346 CAR-T cells at a single fixed dose of 2×106 cells/kg on day 1 at 1st cycle. IBI346 antibody treatment continued until disease progression. Results: Pts enrollment, baseline data and treatment exposure are summarized in Table 1. For both studies, the most common TRAEs were hematological toxicities; no neurotoxicity occurred. For Y2 study, cytokine release syndrome (CRS) occurred in 4 pts (80.0%), all being grade 1-2 with a median time to CRS onset of 11.5 days. For Y1 study, one pt (in 1 mg/kg cohort) experienced continued neutrophil count decrease for ≥14 days after lymphodepletion, which was deemed a dose-limiting toxicity per protocol. No other unexpected AEs occurred. At a median follow up of 5.3 months (m) in Y1 study, 3 of 6 pts (1 pt at 0.3 mg/kg and 2 at 1 mg/kg) achieved partial response (PR), including 1 pt with extramedullary plasmacytomas who maintained PR for 6 m. At a median follow up of 2.3 m in Y2 study, 2/5 pts (1 pt at 0.1 mg/kg and 1 at 0.3 mg/kg) achieved PR or better. More data are needed for valid efficacy evidence. Robust CAR-T cell expansion in peripheral blood (PB) was observed. The median peak CAR copies were 7.725×104 copies/ug genomic DNA (range 0.131×104-17.5×104) which occurred around day 18 (range 11-35) after cell infusion in Y1 study, and were 2.71×104 copies/ug genomic DNA (range 1.58×104-8.2×104) which occurred around day 19 (range 14-22) in Y2 study. Compared with Q3W antibody dosing schema in Y1 study, antibody dosing at QW in Y2 study better maintained antibody concentration. Impressively, CAR-T presence in PB in one pt was detectable up to 150 days (9000 copies) by data cutoff (Jan 30, 2023) in Y2 study.Conclusion: BCMA-targeting modular P329G-CAR-T cell therapy IBI346 was well tolerated and showed preliminary clinical activity in heavily pretreated pts with RRMM. To realize the full potential of this modular CAR-T cell product, the dose and regimen of the P329G antibody and CAR-T cells requires further exploration. Correspondence to Dr. Depei Wu Keywords: Multiple myeloma, CAR-T, B-cell maturation antigen